chr18-23931070-C-A

Variant names:

• chr18-23931070-C-A
• rs1154232
• NM_198129.4:c.8445C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_198129.4(LAMA3):​c.8445C>A​(p.Asn2815Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.198 in 1,610,202 control chromosomes in the GnomAD database, including 32,847 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. N2815N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.16 (2357 hom., cov: 32)
  • Exomes 𝑓: 0.20 (30490 hom.)
• Consequence: LAMA3 NM_198129.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.0170
• Publications: 36 publications found

Genes affected

LAMA3 (HGNC:6483): (laminin subunit alpha 3) The protein encoded by this gene belongs to the laminin family of secreted molecules. Laminins are heterotrimeric molecules that consist of alpha, beta, and gamma subunits that assemble through a coiled-coil domain. Laminins are essential for formation and function of the basement membrane and have additional functions in regulating cell migration and mechanical signal transduction. This gene encodes an alpha subunit and is responsive to several epithelial-mesenchymal regulators including keratinocyte growth factor, epidermal growth factor and insulin-like growth factor. Mutations in this gene have been identified as the cause of Herlitz type junctional epidermolysis bullosa and laryngoonychocutaneous syndrome. Alternative splicing and alternative promoter usage result in multiple transcript variants. [provided by RefSeq, Dec 2014]

LAMA3 Gene-Disease associations (from GenCC):

• junctional epidermolysis bullosa

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
• laryngo-onycho-cutaneous syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• junctional epidermolysis bullosa Herlitz type

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
• junctional epidermolysis bullosa, non-Herlitz type

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Genomics England PanelApp
• generalized junctional epidermolysis bullosa non-Herlitz type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017926991).
• BP6: Variant 18-23931070-C-A is Benign according to our data. Variant chr18-23931070-C-A is described in ClinVar as Benign. ClinVar VariationId is 255575.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.225 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198129.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMA3	NM_198129.4	MANE Select	c.8445C>A	p.Asn2815Lys	missense	Exon 65 of 75	NP_937762.2
	LAMA3	NM_000227.6	MANE Plus Clinical	c.3618C>A	p.Asn1206Lys	missense	Exon 28 of 38	NP_000218.3
	LAMA3	NM_001127717.4		c.8277C>A	p.Asn2759Lys	missense	Exon 64 of 74	NP_001121189.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMA3	ENST00000313654.14	TSL:1 MANE Select	c.8445C>A	p.Asn2815Lys	missense	Exon 65 of 75	ENSP00000324532.8
	LAMA3	ENST00000269217.11	TSL:1 MANE Plus Clinical	c.3618C>A	p.Asn1206Lys	missense	Exon 28 of 38	ENSP00000269217.5
	LAMA3	ENST00000399516.7	TSL:1	c.8277C>A	p.Asn2759Lys	missense	Exon 64 of 74	ENSP00000382432.2

Frequencies

GnomAD3 genomes AF: 0.162 AC: 24679 AN: 151974 Hom.: 2350 Cov.: 32

Gnomad AFR AF: 0.0629

Gnomad AMI AF: 0.0855

Gnomad AMR AF: 0.151

Gnomad ASJ AF: 0.144

Gnomad EAS AF: 0.166

Gnomad SAS AF: 0.238

Gnomad FIN AF: 0.257

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.208

Gnomad OTH AF: 0.153

GnomAD2 exomes AF: 0.192 AC: 48334 AN: 251140 AF XY: 0.196

Gnomad AFR exome AF: 0.0571

Gnomad AMR exome AF: 0.174

Gnomad ASJ exome AF: 0.140

Gnomad EAS exome AF: 0.166

Gnomad FIN exome AF: 0.251

Gnomad NFE exome AF: 0.203

Gnomad OTH exome AF: 0.185

GnomAD4 exome AF: 0.201 AC: 293404 AN: 1458110 Hom.: 30490 Cov.: 31 AF XY: 0.202 AC XY: 146758 AN XY: 725554

African (AFR) AF: 0.0521 AC: 1743 AN: 33470

American (AMR) AF: 0.175 AC: 7813 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.144 AC: 3757 AN: 26118

East Asian (EAS) AF: 0.179 AC: 7120 AN: 39674

South Asian (SAS) AF: 0.238 AC: 20545 AN: 86152

European-Finnish (FIN) AF: 0.245 AC: 13078 AN: 53386

Middle Eastern (MID) AF: 0.134 AC: 774 AN: 5762

European-Non Finnish (NFE) AF: 0.205 AC: 227585 AN: 1108556

Other (OTH) AF: 0.182 AC: 10989 AN: 60282

GnomAD4 genome AF: 0.162 AC: 24696 AN: 152092 Hom.: 2357 Cov.: 32 AF XY: 0.164 AC XY: 12202 AN XY: 74336

African (AFR) AF: 0.0628 AC: 2605 AN: 41500

American (AMR) AF: 0.151 AC: 2307 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.144 AC: 500 AN: 3470

East Asian (EAS) AF: 0.167 AC: 864 AN: 5182

South Asian (SAS) AF: 0.237 AC: 1140 AN: 4816

European-Finnish (FIN) AF: 0.257 AC: 2705 AN: 10516

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.208 AC: 14130 AN: 68000

Other (OTH) AF: 0.159 AC: 337 AN: 2114

Alfa AF: 0.182 Hom.: 8966

Bravo AF: 0.147

TwinsUK AF: 0.219 AC: 811

ALSPAC AF: 0.206 AC: 793

ESP6500AA AF: 0.0622 AC: 274

ESP6500EA AF: 0.199 AC: 1711

ExAC AF: 0.189 AC: 22908

Asia WGS AF: 0.211 AC: 733 AN: 3478

EpiCase AF: 0.190

EpiControl AF: 0.186

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Junctional epidermolysis bullosa gravis of Herlitz (2)
-	-	2	Laryngo-onycho-cutaneous syndrome (2)
-	-	1	Junctional epidermolysis bullosa, non-Herlitz type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	8.3
DANN	Benign	0.91
DEOGEN2	Benign	0.017	T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.51	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.1	T
PhyloP100		-0.017
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.43	N
REVEL	Benign	0.16
Sift	Benign	0.23	T
Sift4G	Benign	0.25	T
Vest4		0.047
MutPred		0.53		Gain of ubiquitination at N2815 (P = 0.0311)
MPC		0.14
ClinPred		0.0015	T
GERP RS		2.6
gMVP		0.43
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1154232; hg19: chr18-21511034; COSMIC: COSV52530831; COSMIC: COSV52530831;